 |
PDBsum entry 1f29
|
|
|
|
|
 |
Contents |
 |
|
|
|
|
|
|
|
|
|
|
|
|
* Residue conservation analysis
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
| |
|
DOI no:
|
Structure
8:831-840
(2000)
|
|
PubMed id:
|
|
|
|
|
|
| |
|
A target within the target: probing cruzain's P1' site to define structural determinants for the Chagas' disease protease.
|
|
L.S.Brinen,
E.Hansell,
J.Cheng,
W.R.Roush,
J.H.McKerrow,
R.J.Fletterick.
|
|
|
|
|
| |
ABSTRACT
|
|
|
|
| |
|
|
BACKGROUND: Cysteine proteases of the papain superfamily are present in nearly
all groups of eukaryotes and play vital roles in a wide range of biological
processes and diseases, including antigen and hormone processing, bacterial
infection, arthritis, osteoporosis, Alzheimer's disease and cancer-cell
invasion. Because they are critical to the life-cycle progression of many
pathogenic protozoa, they represent potential targets for selective inhibitors.
Chagas' disease, the leading cause of death due to heart disease in Latin
American countries, is transmitted by Trypanosoma cruzi. Cruzain is the major
cysteine protease of T cruzi and has been the target of extensive
structure-based drug design. RESULTS: High-resolution crystal structures of
cruzain bound to a series of potent phenyl-containing vinyl-sulfone, sulfonate
and sulfonamide inhibitors have been determined. The structures show a
consistent mode of interaction for this family of inhibitors based on a covalent
Michael addition formed at the enzyme's active-site cysteine, hydrophobic
interactions in the S2 substrate-binding pocket and a strong constellation of
hydrogen bonding in the S1' region. CONCLUSIONS: The series of
vinyl-sulfone-based inhibitors examined in complex with cruzain was designed to
probe recognition and binding potential of an aromatic-rich region of the
enzyme. Analysis of the interactions formed shows that aromatic interactions
play a less significant role, whereas the strength and importance of hydrogen
bonding in the conformation adopted by the inhibitor upon binding to the enzyme
was highlighted. A derivative of one inhibitor examined is currently under
development as a therapeutic agent against Chagas' disease.
|
|
|
|
|
|
| |
Selected figure(s)
|
|
|
|
| |
|
|
|
|
Figure 6.
Figure 6. Surface representation of the cruzain active-site
region. Hydrophobic residues are indicated in green. (Note that
the sides of the S2 pocket are lined with hydrophobic patches.)
The surfaces of amino acids of interest (see text) are labeled
and color coded: Gln19 and His159, cyan; Asp158 and Ser139,
magenta; Cys25 and Met142, yellow. Inhibitor molecules are
displayed as sticks. (a) VSI, (b) VSII, (c) VSIII, (d) VSIV.
This figure was prepared with the program GRASP [44].
|
|
|
|
|
|
| |
The above figure is
reprinted
by permission from Cell Press:
Structure
(2000,
8,
831-840)
copyright 2000.
|
|
| |
Figure was
selected
by the author.
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
 |
 |
|
Literature references that cite this PDB file's key reference
|
|
|
| |
PubMed id
|
|
Reference
|
|
|
|
|
|
H.C.Castro,
P.A.Abreu,
R.B.Geraldo,
R.C.Martins,
R.Dos Santos,
N.I.Loureiro,
L.M.Cabral,
and
C.R.Rodrigues
(2011).
Looking at the proteases from a simple perspective.
|
| |
J Mol Recognit,
24,
165-181.
|
|
|
|
|
|
|
J.D.Durrant,
H.Keränen,
B.A.Wilson,
and
J.A.McCammon
(2010).
Computational identification of uncharacterized cruzain binding sites.
|
| |
PLoS Negl Trop Dis,
4,
e676.
|
|
|
|
|
|
|
K.Brak,
I.D.Kerr,
K.T.Barrett,
N.Fuchi,
M.Debnath,
K.Ang,
J.C.Engel,
J.H.McKerrow,
P.S.Doyle,
L.S.Brinen,
and
J.A.Ellman
(2010).
Nonpeptidic tetrafluorophenoxymethyl ketone cruzain inhibitors as promising new leads for Chagas disease chemotherapy.
|
| |
J Med Chem,
53,
1763-1773.
|
|
|
PDB code:
|
|
|
|
|
|
|
|
Y.T.Chen,
L.S.Brinen,
I.D.Kerr,
E.Hansell,
P.S.Doyle,
J.H.McKerrow,
and
W.R.Roush
(2010).
In vitro and in vivo studies of the trypanocidal properties of WRR-483 against Trypanosoma cruzi.
|
| |
PLoS Negl Trop Dis,
4,
0.
|
|
|
PDB code:
|
|
|
|
|
|
|
|
I.D.Kerr,
J.H.Lee,
C.J.Farady,
R.Marion,
M.Rickert,
M.Sajid,
K.C.Pandey,
C.R.Caffrey,
J.Legac,
E.Hansell,
J.H.McKerrow,
C.S.Craik,
P.J.Rosenthal,
and
L.S.Brinen
(2009).
Vinyl sulfones as antiparasitic agents and a structural basis for drug design.
|
| |
J Biol Chem,
284,
25697-25703.
|
|
|
PDB codes:
|
|
|
|
|
|
|
|
R.Huang,
X.Que,
K.Hirata,
L.S.Brinen,
J.H.Lee,
E.Hansell,
J.Engel,
M.Sajid,
and
S.Reed
(2009).
The cathepsin L of Toxoplasma gondii (TgCPL) and its endogenous macromolecular inhibitor, toxostatin.
|
| |
Mol Biochem Parasitol,
164,
86-94.
|
|
|
|
|
|
|
C.M.Stack,
C.R.Caffrey,
S.M.Donnelly,
A.Seshaadri,
J.Lowther,
J.F.Tort,
P.R.Collins,
M.W.Robinson,
W.Xu,
J.H.McKerrow,
C.S.Craik,
S.R.Geiger,
R.Marion,
L.S.Brinen,
and
J.P.Dalton
(2008).
Structural and functional relationships in the virulence-associated cathepsin L proteases of the parasitic liver fluke, Fasciola hepatica.
|
| |
J Biol Chem,
283,
9896-9908.
|
|
|
PDB code:
|
|
|
|
|
|
|
|
Y.T.Chen,
R.Lira,
E.Hansell,
J.H.McKerrow,
and
W.R.Roush
(2008).
Synthesis of macrocyclic trypanosomal cysteine protease inhibitors.
|
| |
Bioorg Med Chem Lett,
18,
5860-5863.
|
|
|
|
|
|
|
F.C.dos Reis,
W.A.Júdice,
M.A.Juliano,
L.Juliano,
J.Scharfstein,
and
A.P.Lima
(2006).
The substrate specificity of cruzipain 2, a cysteine protease isoform from Trypanosoma cruzi.
|
| |
FEMS Microbiol Lett,
259,
215-220.
|
|
|
|
|
|
|
T.Hogg,
K.Nagarajan,
S.Herzberg,
L.Chen,
X.Shen,
H.Jiang,
M.Wecke,
C.Blohmke,
R.Hilgenfeld,
and
C.L.Schmidt
(2006).
Structural and functional characterization of Falcipain-2, a hemoglobinase from the malarial parasite Plasmodium falciparum.
|
| |
J Biol Chem,
281,
25425-25437.
|
|
|
PDB code:
|
|
|
|
|
|
|
|
Y.A.Sabnis,
P.V.Desai,
P.J.Rosenthal,
and
M.A.Avery
(2003).
Probing the structure of falcipain-3, a cysteine protease from Plasmodium falciparum: comparative protein modeling and docking studies.
|
| |
Protein Sci,
12,
501-509.
|
|
|
|
|
|
|
D.C.Greenbaum,
W.D.Arnold,
F.Lu,
L.Hayrapetian,
A.Baruch,
J.Krumrine,
S.Toba,
K.Chehade,
D.Brömme,
I.D.Kuntz,
and
M.Bogyo
(2002).
Small molecule affinity fingerprinting. A tool for enzyme family subclassification, target identification, and inhibitor design.
|
| |
Chem Biol,
9,
1085-1094.
|
|
|
|
|
|
|
G.Lalmanach,
A.Boulangé,
C.Serveau,
F.Lecaille,
J.Scharfstein,
F.Gauthier,
and
E.Authié
(2002).
Congopain from Trypanosoma congolense: drug target and vaccine candidate.
|
| |
Biol Chem,
383,
739-749.
|
|
|
|
|
|
|
M.Klemba,
and
D.E.Goldberg
(2002).
Biological roles of proteases in parasitic protozoa.
|
| |
Annu Rev Biochem,
71,
275-305.
|
|
|
|
|
|
|
W.A.Judice,
M.H.Cezari,
A.P.Lima,
J.Scharfstein,
J.R.Chagas,
I.L.Tersariol,
M.A.Juliano,
and
L.Juliano
(2001).
Comparison of the specificity, stability and individual rate constants with respective activation parameters for the peptidase activity of cruzipain and its recombinant form, cruzain, from Trypanosoma cruzi.
|
| |
Eur J Biochem,
268,
6578-6586.
|
|
|
|
|
|
The most recent references are shown first.
Citation data come partly from CiteXplore and partly
from an automated harvesting procedure. Note that this is likely to be
only a partial list as not all journals are covered by
either method. However, we are continually building up the citation data
so more and more references will be included with time.
Where a reference describes a PDB structure, the PDB
code is
shown on the right.
|
|
Links
